1,2,4-Oxadiazoles, and in particular, 3,5-disubstituted-1,2,4-oxadiazoles, have been shown to have biological activity in pharmaceutical and agricultural fields. For example, 3,5-disubstituted-1,2,4-oxadiazoles are disclosed as disease suppression and treatment agents (U.S. Pat. No. 6,992,096), as therapeutic agents for hepatitis C (Pub. No. US 2005/0075375 A1), and for nematode control in agriculture (Pub. No. US 2009/0048311 A1).
3,5-Disubstituted-1,2,4-oxadiazoles can be prepared in a number of ways. One is preparation of 3,5-disubstituted-1,2,4-oxadiazoles via reaction of an aryl amide oxime and an acyl chloride (Pub. No. US 2008/0269236 A1, U.S. Pat. No. 7,678,922, Pub. No. US 2008/0113961 A1, JP 2008120794 and Bioorg. Med Chem Lett. 19, 4410). Another method for preparation of 3,5-disubstituted-1,2,4-oxadiazoles is reaction of a benzamide oxime or propionamidoxime with a carboxylic acid or ester (WO 2011/141326, WO 2012/012477, and WO 2011/085406). Other routes to 3,5-disubsituted-1,2,4-oxadiazoles include reaction of a benzamide with a Weinreb amide (Pub. No. US 2010/0048648 A1) and reaction of a hydroxyamyl halide and a nitrile (U.S. Pat. No. 3,211,742).
While methods for preparing 3,5-disubstituted-1,2,4-oxadiazoles exist, alternative routes that may result in a more efficient synthesis are highly desirable. In particular, synthetic processes with fewer isolation steps and/or solvents can be more efficient and less expensive. In addition, processes that reduce and/or eliminate solids handling, reduce reaction time and/or use fewer reaction intermediates can significantly reduce capital equipment expenditures in large scale manufacturing. Finally, the use of milder reaction conditions (e.g. lower temperatures) may prevent degradation of desired intermediates and products resulting in fewer unwanted side products and ultimately a better product purity profile.
Citation of any reference above is not to be construed as an admission that such reference is prior art to the present application.